Determinants of Timely Access to Recanalization Treatments and Outcomes in Pediatric Ischemic Stroke.

BACKGROUND: Timely revascularization in acute arterial ischemic stroke (AIS) is paramount for optimal outcomes. However, factors causing treatment delays in pediatric AIS remain understudied. We investigated determinants affecting the time from symptom onset or last-known-well to the start of recanalization treatment in pediatric AIS. METHODS: We conducted an ancillary analysis of the French KID-CLOT study (The National Retrospective Study of Recanalization Treatments in Pediatric Arterial Ischemic Stroke), considering patients with pediatric AIS receiving recanalization treatments (IV thrombolysis IVT and mechanical thrombectomy) from 2015 to 2018. The study assessed prehospital triage's impact, direct versus transferred admissions, and unit type (pediatric versus adult) on treatment delay and clinical outcomes using modified Rankin Scale at 1 year. RESULTS: Among 68 patients (median age, 11 [IQR, 4-16]; initial PedNIHSS, 13 [IQR, 7-19]), treatment modalities were IVT (n=31), and mechanical thrombectomy (n=23), and IVT+mechanical thrombectomy (n=14). Prehospital triage significantly reduced last-known-well to treatment delay (overall, 229 versus 270 minutes; P=0.01), most notably for and mechanical thrombectomy (P<0.001). There was no substantial delay difference between direct and transferred admissions, or between unit types, although a trend favored adult units (370.3 versus 436.73 minutes; P=0.06). Prehospital triage correlated with improved outcomes, with a shift to lower modified Rankin Scale scores (P=0.021). CONCLUSIONS: For pediatric AIS treated with reperfusion therapy, prehospital triage emerges as a pivotal factor in reducing treatment delays and enhancing outcomes. These findings underscore the need for a dedicated prehospital stroke protocol for children. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03887143.

Infection and Pediatric Arterial Ischemic Stroke Presumably Related to Focal Cerebral Arteriopathy: Data From the COVID-19 Pandemic.

BACKGROUND: Infection may trigger pediatric arterial ischemic stroke (PAIS), notably when related to focal cerebral arteriopathy. Community- and individual-level nonpharmaceutical interventions during the COVID-19 pandemic resulted in a major decrease in pediatric viral infections. We explored the consequences on the incidence of PAIS. METHODS: Using national public health databases, we identified children hospitalized between 2015 and 2022 with PAIS. Using an age proxy (29 days to 7 years) and excluding patients with cardiac and hematologic conditions, we focused on children with PAIS presumably related to focal cerebral arteriopathy or with no definite cause. Considering the delay between infection and PAIS occurrence, we compared a prepandemic reference period, a period with nonpharmaceutical interventions, and a post-nonpharmaceutical intervention period. RESULTS: Interrupted time-series analyses of the monthly incidence of PAIS in this group showed a significant decrease in the nonpharmaceutical intervention period compared with the prepandemic period: -33.5% (95% CI, -55.2%, -1.3%); P=0.043. CONCLUSIONS: These data support the association between infection and PAIS presumably related to focal cerebral arteriopathy.

Stroke without cerebral arteriopathy in sickle cell disease children: causes and treatment.

Cerebral arteriopathy (CA) in children with sickle cell disease (SCD) is classically described as chronic stenosis of arteries in the anterior brain circulation, leading to ischemic stroke. Some studies have, however, reported strokes in children with SCD but without CA. In order to better understand the etiology and risk factors of these strokes, we retrospectively analyzed ischemic strokes occurring in a large cohort of children over a 13-year period. Between 2007 and 2020, 25 of 1,500 children with SCD had an ischemic stroke in our center. Among them, 13 (52%) had CA, described as anatomical arterial stenosis, while 12 (48%) did not. Patients with stroke without CA were older than patients with stroke attributed to SCD-CA (9.0 years old vs. 3.6 years old; P=0.008), and more frequently had SC genotype (25% vs. 0%, respectively). Their strokes more frequently involved the posterior circulation, with cerebellar involvement in 42%. Retained stroke etiologies in patients without typical SCD-related CA were reversible cerebral vasoconstriction syndrome, cerebral fat embolism, arterial thrombosis or thromboembolism, hyperviscosity, vasculitis in a context of infectious meningo-encephalitis, and severe hemodynamic failure. No recurrence was observed in the 24 months following stroke, even though 67% of the patients in this group were no longer receiving exchange transfusions. In conclusion, in a cohort of pediatric SCD patients with an efficient stroke screening strategy, half of the ischemic strokes that occurred were related to causes other than CA. They affected a different population of SCD children and systematic long-term transfusion programs may not be necessary in these cases.

Biallelic variants in NOS3 and GUCY1A3, the two major genes of the nitric oxide pathway, cause moyamoya cerebral angiopathy.

BACKGROUND: Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA. METHODS: Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses. RESULTS: Causative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia. CONCLUSIONS: We show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.

Neurologic Outcomes and Quality of Life in Children After Extracorporeal Membrane Oxygenation.

RATIONALE: Use of life support with extracorporeal membrane oxygenation (ECMO) is associated with brain injury. However, the consequences of these injuries on subsequent neurologic development and health-related quality of life (HRQoL) are poorly described in children. OBJECTIVES: The aim of this preliminary study was to describe short- and long-term neurologic outcomes in survivors of ECMO, as well as their HRQoL. DESIGN: Retrospective identified cohort with contemporary evaluations. SETTING: Necker Children's Hospital academic PICU. PATIENTS: Forty survivors who underwent ECMO (October 2014 to January 2020) were included in follow-up assessments in May 2021. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We first reviewed the outcomes of ECMO at the time of PICU discharge, which included a summary of neurology, radiology, and Pediatric Overall/Cerebral Performance Category (POPC/PCPC) scores. Then, in May 2021, we interviewed parents and patients to assess HRQoL (Pediatric Quality of Life Inventory [PedsQL]) and POPC/PCPC for children 3 years old or older, and Denver II test (DTII) for younger children. An evaluation of DTII in the youngest patients 1 year after ECMO decannulation was also added. Median age at ECMO was 1.4 years (interquartile range [IQR], 0.4-6 yr). Thirty-five children (88%) underwent a venoarterial ECMO. At PICU discharge, 15 of 40 patients (38%) had neurologic impairment. Assessment of HRQoL was carried out at median of 1.6 years (IQR, 0.7-3.3 yr) after PICU discharge. PedsQL scores were over 70 of 100 for all patients (healthy peers mean results: 80/100), and scores were like those published in patients suffering with chronic diseases. In May 2021, seven of 15 patients had a normal DTII, and 36 of 40 patients had a POPC/PCPC score less than or equal to 3. CONCLUSIONS: None of our patients presented severe disability at long term, and HRQoL evaluation was reassuring. Considering the risk of neurologic impairment after ECMO support, a systematic follow-up of these high-risk survivor patients would be advisable.

Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management.

OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.

Clinical and radiological description of 120 pediatric stroke-like episodes.

BACKGROUND AND PURPOSE: Stroke-like episodes (SLEs) are defined as acute onset of neurological symptoms mimicking a stroke and radiological lesions non-congruent to vascular territory. We aimed to analyze the acute clinical and radiological features of SLEs to determine their pathophysiology. METHODS: We performed a monocenter retrospective analysis of 120 SLEs in 60 children over a 20-year period. Inclusion criteria were compatible clinical symptoms and stroke-like lesions on brain magnetic resonance imaging (MRI; performed for all 120 events) with focal hyperintensity on diffusion-weighted imaging in a non-vascular territory. RESULTS: Three groups were identified: children with mitochondrial diseases (n = 22) involving mitochondrial DNA mutations (55%) or nuclear DNA mutations (45%); those with other metabolic diseases or epilepsy disorders (n = 22); and those in whom no etiology was found despite extensive investigations (n = 16). Age at first SLE was younger in the group with metabolic or epilepsy disorders (18 months vs. 128 months; p < 0.0001) and an infectious trigger was more frequent (69% vs. 20%; p = 0.0001). Seizures occurred in 75% of episodes, revealing 50% episodes of SLEs and mainly leading to status epilepticus (90%). Of the 120 MRI scans confirming the diagnosis, 28 were performed within a short and strict 48-h period and were further analyzed to better understand the underlying mechanisms. The scans showed primary cortical hyperintensity (n = 28/28) with decreased apparent diffusion coefficient in 52% of cases. Systematic hyperperfusion was found on spin labeling sequences when available (n = 18/18). CONCLUSION: Clinical and radiological results support the existence of a vicious circle based on two main mechanisms: energy deficit and neuronal hyperexcitability at the origin of SLE.

Cerebral sinovenous thrombosis associated with head/neck infection in children: Clues for improved management.

AIM: To compare paediatric patients with cerebral sinovenous thrombosis (CSVT) with and without head/neck infection to improve management of the condition. METHOD: We conducted a bicentric retrospective study of consecutive children (neonates excluded) with radiologically confirmed CSVT, comparing children with a concurrent head/neck infection and children with other causes. RESULTS: A total of 84 consecutive patients (46 males and 38 females) with a median age of 4 years 6 months (range 3 months-17 years 5 months) were included. Associated head/neck infection was identified in 65.4% of cases and represented the main identified CSVT aetiology. Children in the head/neck infection group displayed a milder clinical presentation and less extensive CSVT. Median time to complete recanalization was significantly shorter in this group (89 days [interquartile range 35-101] vs 112.5 days [interquartile range 83-177], p = 0.005). These findings were even more pronounced in the subgroup of patients with otogenic infection and no neurological sign. INTERPRETATION: As CSVT in the setting of an otogenic infection and no neurological sign seems to represent a milder condition with a shorter course, these results suggest adapting current recommendations: consider earlier control imaging in paediatric otogenic CSVT, and shorter anticoagulant treatment if recanalization is obtained. WHAT THIS PAPER ADDS: Children with cerebral sinovenous thrombosis related to head/neck infections have a milder clinical presentation. They also have a shorter recanalization time, especially if there is otogenic infection without neurological symptoms.

Neurological features related to influenza virus in the pediatric population: a 3-year monocentric retrospective study.

Influenza virus is generally characterized by fever, myalgia, and respiratory symptoms. Neurological entities have already been described, such as acute necrotizing encephalitis (ANE). We aimed to highlight the non-exceptional nature and explore the clinical spectrum and evolution of neurological features related to influenza virus in children. This monocentric observational study included patients under 18 years old, positive for influenza virus, between January 2017 and April 2019 in a pediatric university hospital. Patients were classified into two groups: those with or without a previous significant neurological or metabolic disorder. Two hundred eighty-nine children were identified with influenza infection. Thirty seven had a neurological manifestation: 14 patients who had previous significant neurological or metabolic disorder and 23 patients with no medical history. We identified several clinical patterns: 22 patients had seizures, 7 behavior disorders, 5 disturbances of consciousness, and 3 motor deficits. Four were diagnosed with a known influenza-associated neurological syndrome: 1 ANE, 1 cytotoxic lesion of the corpus callosum, 1 hemiconvulsion-hemiplegia-epilepsia syndrome, and 1 recurrent encephalitis in the context of a RANBP2 mutation. The neurological outcome was favorable in most cases. None of the patients with previous significant disorder retained sequalae or had a recurrence. Two patients had a fatal outcome, and both had a predisposing disorder. CONCLUSION: Various neurological manifestations can be associated with influenza virus. Certain entities led to a poor prognosis, but in most cases, symptoms improved within a few days. The severity of the neurological manifestations correlated with previous neurological or metabolic disorders. WHAT IS KNOWN: • Influenza viruses are well known pathogens with a seasonal epidemic evolution, particularly affecting children. These viruses cause acute fever with respiratory symptoms, associated with myalgia and headaches. Neurological presentation in influenza-virus infection is a well-established possibility as influenza virus is considered to be responsible for 27 to 36% of childhood encephalitis. Some specific and severe entity as acute necrotizing encephalitis, cytotoxic lesion of the corpus callosum, or Hemiconvulsion-hemiplegia-epilepsy syndrome are well described. WHAT IS NEW: • In a French monocentric cohort of 37 children with influenza-related neurologic manifestations, the majority of these manifestations, including seizure, drowsiness, motor deficiency, hallucination… are self limiting and do not lead to after-effects. In rare cases (4/37), they may reveal severe encephalitis requiring rapid and appropriate treatment. Otherwise, comparison of a group of 14 children with underlying neurological or metabolic disorder with a group of 23 children free of any significant disorder show that the severity of the neurological manifestations was largely related to previous neurological or metabolic disorders highlighting the importance of vaccination in this population.

Severe and fatal neonatal infections linked to a new variant of echovirus 11, France, July 2022 to April 2023.

We report nine severe neonatal infections caused by a new variant of echovirus 11. All were male, eight were twins. At illness onset, they were 3-5 days-old and had severe sepsis and liver failure. This new variant, detected in France since April 2022, is still circulating and has caused more fatal neonatal enterovirus infections in 2022 and 2023 (8/496; 1.6%, seven associated with echovirus 11) compared with 2016 to 2021 (7/1,774; 0.4%). National and international alerts are warranted.